title: Discovery of novel, potent and bioavailable proline-urea based macrocyclic HCV NS3/4A protease inhibitors.
abstract: A novel series of P3-truncated macrocyclic HCV NS3/4A protease inhibitors containing a P2 proline-urea or carbamate scaffold was synthesized. Very potent inhibitors were obtained through the optimization of the macrocycle size, urea and proline substitution, and bioisosteric replacement of the P1 carboxylic acid moiety. Variation of the lipophilicity by introduction of small lipophilic substituents resulted in improved PK profiles, ultimately leading to compound 13Bh, an extremely potent (K(i)=0.1 nM, EC(50)=4.5 nM) and selective (CC(50) (Huh-7 cells)>50 microM) inhibitor, displaying an excellent PK profile in rats characterized by an oral bioavailability of 54% and a high liver exposure after oral administration.
authors.affiliation: Tibotec BVBA, Gen. De Wittelaan L11 B3, B-2800 Mechelen, Belgium.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Vendeville
authors.forename: Magnus
authors.initials: M
authors.lastname: Nilsson
authors.forename: Herman
authors.initials: H
authors.lastname: de Kock
authors.forename: Tse-I
authors.initials: TI
authors.lastname: Lin
authors.forename: Dmitry
authors.initials: D
authors.lastname: Antonov
authors.forename: Björn
authors.initials: B
authors.lastname: Classon
authors.forename: Susana
authors.initials: S
authors.lastname: Ayesa
authors.forename: Vladimir
authors.initials: V
authors.lastname: Ivanov
authors.forename: Per-Ola
authors.initials: PO
authors.lastname: Johansson
authors.forename: Pia
authors.initials: P
authors.lastname: Kahnberg
authors.forename: Anders
authors.initials: A
authors.lastname: Eneroth
authors.forename: Kristina
authors.initials: K
authors.lastname: Wikstrom
authors.forename: Lotta
authors.initials: L
authors.lastname: Vrang
authors.forename: Michael
authors.initials: M
authors.lastname: Edlund
authors.forename: Stefan
authors.initials: S
authors.lastname: Lindström
authors.forename: Wim
authors.initials: W
authors.lastname: Van de Vreken
authors.forename: David
authors.initials: D
authors.lastname: McGowan
authors.forename: Abdellah
authors.initials: A
authors.lastname: Tahri
authors.forename: Lili
authors.initials: L
authors.lastname: Hu
authors.forename: Oliver
authors.initials: O
authors.lastname: Lenz
authors.forename: Frederic
authors.initials: F
authors.lastname: Delouvroy
authors.forename: Marleen
authors.initials: M
authors.lastname: Van Dooren
authors.forename: Natalie
authors.initials: N
authors.lastname: Kindermans
authors.forename: Dominique
authors.initials: D
authors.lastname: Surleraux
authors.forename: Piet
authors.initials: P
authors.lastname: Wigerinck
authors.forename: Asa
authors.initials: A
authors.lastname: Rosenquist
authors.forename: Bertil
authors.initials: B
authors.lastname: Samuelsson
authors.forename: Kenneth
authors.initials: K
authors.lastname: Simmen
authors.forename: Pierre
authors.initials: P
authors.lastname: Raboisson
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology / Q000627:therapeutic use; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D016174:Hepacivirus / Q000187:drug effects*; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D011392:Proline / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D011392:Proline; D015842:Serine Proteinase Inhibitors; D014508:Urea; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C093542:NS4 protein, hepatitis C virus